The present invention relates to a method for producing and purifying N-carbamate-protected xcex2-aminoepoxide with a specific steric configuration {(2R, 3S) or (2S, 3R)} and a method for producing the crystal. The invention also relates to a method for producing and purifying N-carbamate-protected xcex2-aminoalcohol with a specific steric configuration {(2R, 3S) or (2S, 3R)}.
The N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2) is a useful compound as a pharmaceutical intermediate: 
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing a hetero atom in these carbon backbones; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)}.
It is known for example that (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide is useful as an intermediate of HIV protease inhibitors and renin inhibitors (see for example Raddatz et al., Journal of Medicinal Chemistry, 1991, 34, 11,3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update).
It has been known that N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2) can be synthesized according to the following pathway. 
{in the formula, R and A represent the same meanings described above; X represents halogen atom}.
When (3S)-N-carbamate-protected xcex1-halomethylketone as the compound represented by the general formula (4) is used as a starting material, for example, the starting material is reduced to afford (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol, followed by treatment with a base, to afford (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide.
Similarly, when (3R)-N-carbamate-protected xcex1-halomethylketone is used as a starting material, the starting material is reduced to afford (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol, followed by treatment with a base, to afford (2S, 3R)-N-carbamate-protected aminoepoxide.
Herein, the reduction of N-carbamate-protected xcex1-halomethylketone with an appropriate reducing agent involves the generation of the diastereomer as a byproduct.
For example, the reduction of (3S)-N-carbamate-protected xcex1-halomethylketone represented by the general formula (13) involves the generation of the diastereomer (2S, 3S)-N-carbamate-protected xcex2-aminoalcohol (7) as a byproduct.
Upon treatment with a base, the byproduct is converted to as (2S, 3S)-N-carbamate-protected xcex2-aminoepoxide (11) as the diastereomer of the objective compound (see the following scheme). 
{in the formulas, R, A, X represent the same meanings as described above.}
More specifically, for example, it is reported that the reduction of, e.g., (3S)-3-tert-butoxycarbonylamino-1-halo-4-phenyl-2-butane in ether with lithium aluminum tri-tert-butoxyhydride involves the generation of the diastereomer (2S, 3S)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4phenylbutane at a ratio of about 1 mol equivalent to 5 to 8 mol equivalents of the objective (2R, 3S) compound (see P. Raddatz et al., J. Med. Chem., 1991, 34, 11, 3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update). (2R, 3S)-3-tert-butoxycarbonylamino 1,2-epoxy-4-phenylbutane afforded by an additional treatment with a base also contains the diastereomer at about the same ratio.
The above references disclose methods for separating (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol or (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide by silica gel chromatography or high-performance liquid chromatography, but the methods require the use of vast amounts of expensive carriers and solvents and take a long time due to the complex procedures. Accordingly, these methods are not industrially appropriate.
Of the references above, the latter reference discloses on page 3 that because (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol or (2R, 3S)N-carbamate-protected xcex2-aminoepoxide is at a lower melting point and a higher solubility than those of the diastereomer, the ratio of the diastereomer to the objective compound can be reduced to 94:6, at most, by purification with crystallization and that no more purification thereof by recrystallization is possible.
Further, the technique for removing other impurities is not necessarily satisfactory. Hence, the development of an industrial method for producing highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide has been desired.
It is an object of the present invention to provide an industrial method for producing (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide (including the crystal) and N-carbamate-protected xcex2-aminoalcohol.
The present inventors have made investigations so as to solve the problem. The following findings have been found.
1) By dissolving (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity or an optical isomer thereof in a solvent including at least one or more selected from aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, thereby removing insoluble matters, the diastereomer as an impurity is highly separated and removed.
2) By treating (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide containing at least the diastereomer as an impurity or an optical isomer thereof with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative, and separating and removing the resulting derivative in water or an aqueous mixture solvent, the diastereomer as an impurity is highly separated and removed.
3) By crystallizing (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide or an optical isomer thereof in an aqueous mixture solvent, a more highly pure crystal of the epoxide can be obtained.
Accordingly, the object of the present invention, and others, may be accomplished with a method for producing N-carbamate-protected xcex2-aminoepoxide crystal including:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity and being represented by the general formula (1), in a solvent including at least one or more selected from aromatic hydrocarbon solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble matters: 
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in these carbon backbones; X represents halogen atom; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(b) treating the N-carbamate-protected xcex2-aminoalcohol represented by the general formula (1) with a base, thereby converting the N-carbamate-protected xcex2-aminoalcohol to N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2): 
{in the formula, R, A and * represent the same meanings as described above; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(c) treating the N-carbamate-protected xcex2-aminoepoxide containing at least the diastereomer as an impurity and being represented by the general formula (2) with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative represented by the general formula (3): 
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in these carbon backbones; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R) 
{in the formula, A and * represent the same meaning as described above; the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S)}, and, if necessary, separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and
(d) crystallizing the N-carbamate-protected aminoepoxide represented by the general formula (2) in an aqueous mixture solvent.
Another embodiment of the invention provides a crystal of N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the invention provides a method for producing an N-carbamate-protected xcex2-aminoalcohol, which includes:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol including at least a diastereomer thereof as an impurity and represented by the formula (1) in at least one solvent selected from the group including aromatic hydrocarbon, aryl halide, saturated hydrocarbon, aqueous mixture, acetone and 2-propanol, to remove insoluble materials: 
wherein in formula (1):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone;
X represents halogen atom; and
* represents asymmetric carbon atom;
wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide, which includes:
(a) dissolving N-carbamate-protected xcex2-aminoalcohol including at least a diastereomer thereof as an impurity and represented by the formula (1), in at least one solvent selected from the group including aromatic hydrocarbon, aryl halide, saturated hydrocarbon, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble materials: 
wherein in formula (1):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone;
X represents halogen atom; and
* represents asymmetric carbon atom;
wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R);
(b) treating the N-carbamate-protected xcex2-aminoalcohol represented by the formula (1) with a base, thereby converting the N-carbamate-protected xcex2-aminoalcohol to N-carbamate-protected xcex2-aminoepoxide represented by the formula (2): 
wherein in formula (2), R, A and * have the same meanings as recited above; and wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide crystal, which includes:
(c) treating the N-carbamate-protected xcex2-aminoepoxide including at least a diastereomer thereof as an impurity and represented by the formula (2) with an acid, thereby converting the diastereomer to oxazolidin-2-one derivative represented by the formula (3): 
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; and wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R); 
wherein in formula (3), A and * have the same meaning as recited above; and wherein the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S), and optionally separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and
(d) crystallizing the N-carbamate-protected aminoepoxide represented by the formula (2) in an aqueous mixture solvent.
Another embodiment of the present invention provides a crystal of the N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the present invention provides a method for producing an N-carbamate-protected xcex2-aminoepoxide crystal, which includes:
(d) crystallizing the N-carbamate-protected xcex2-aminoepoxide represented by the formula (2) in an aqueous mixture solvent: 
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R).
Another embodiment of the present invention provides a crystal of N-carbamate-protected xcex2-aminoepoxide represented by the formula (2), which is produced by the above method.
Another embodiment of the present invention provides a method for producing an N-carbamate-protected aminoepoxide, which includes:
(c) treating the N-carbamate-protected aminoepoxide including at least a diastereomer thereof as an impurity and being represented by the formula (2) with a solid acid insoluble in solvents, thereby converting the diastereomer to oxazolidin-2-one derivative represented by the formula (3): 
wherein in formula (2):
R represents a lower alkyl group, benzyl group or fluorenylmethyl group;
A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in the carbon backbone; and
* represents asymmetric carbon atom; wherein the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R); 
wherein in formula (3), A and * have the same meaning as recited above; and wherein the steric configuration at 4- and 5-positions is (4S, 5R) or (4R, 5S); and
separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent.
By the methods of the present invention, highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide or (2R, 3S) or (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol can be efficiently produced.
Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood from the following detailed description of the preferred embodiments of the invention.
In the present specification, (2R, 3S)-N-carbamate-protected xcex2-aminoalcohol is sometimes abbreviated as (2R, 3S) alcohol; and the diastereomer as an impurity is sometimes abbreviated as (2S, 3S) alcohol. 
Additionally, (2S, 3R)-N-carbamate-protected xcex2-aminoalcohol is sometimes abbreviated as (2S, 3R) alcohol; and the diastereomer as an impurity is sometimes abbreviated as (2R, 3R) alcohol. 
Still additionally, (2R, 3S)-N-carbamate-protected xcex2-aminoepoxide is sometimes abbreviated as (2R, 3S) epoxide; and the diastereomer as an impurity is sometimes abbreviated as (2S, 3S) epoxide. 
Furthermore, (2S, 3R)-N-carbamate-protected xcex2-aminoepoxide is sometimes abbreviated as (2S, 3R) epoxide; and the diastereomer as an impurity is sometimes abbreviated as (2R, 3R) epoxide. 
In the formulas in accordance with the invention, X represents halogen atom. As the halogen atom, chlorine atom and bromine atom are preferable; and chlorine atom is particularly preferable.
In the formulas in accordance with the invention, R represents a lower alkyl group, benzyl group or fluorenylmethyl group. As the R, a lower alkyl group is preferable. The lower alkyl group includes an alkyl group with 1 to 8 carbon atoms, preferably an alkyl group with 1 to 4 carbon atoms. Methyl group, ethyl group and tert-butyl group are particularly preferred.
As the R, tert-butyl group is most particularly preferable.
In the formulas in accordance with the invention, A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing a hetero atom in these carbon backbones. Preferably, A represents an unsubstituted or substituted alkyl group with 1 to 8 carbon atoms, an unsubstituted or substituted aryl group with 6 to 13 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 18 carbon atoms, or a group containing a hetero atom in these carbon backbones. When A is substituted one or more groups as above-mentioned, the substituent is not particularly limited unless it especially affect the reaction of the invention. The substituent includes, for example, alkoxyl group (preferably with 1 to 7 carbon atoms), nitro group, alkyl group (preferably with 1 to 6 carbon atoms), and halogen atom.
The group containing one or more hetero atoms in these carbon backbones includes, for example, methylthioethyl group, t-butylthiomethyl group, tritylthiomethyl group, (p-methylbenzyl)thiomethyl group, (p-methoxybenzyl)thiomethyl group, t-butoxymethyl group, benzyloxymethyl group, t-butoxyethyl group, benzyloxyethyl group, 4-(t-butoxy)phenylmethyl group, 4-benzyloxyphenylmethyl group and phenylthiomethyl group.
Such groups can be introduced by using for example amino acid as a raw material. In case that A is methyl group, for example, alanine is used as a raw material; in case that A is isopropyl group, valine is used as a raw material; in case that A is 2-methylpropyl group, leucine is used as a raw material; in case that A is 1-methylpropyl group, isoleucine is used as a raw material; in case that A is benzyl group, phenylalanine is used as a raw material; in case that A is methylthioethyl group, methionine is used as a raw material.
Additionally, A may satisfactorily be a group introduced from a raw material amino acid with a functional group in the side chain of the amino acid under protection, for example S-t-butylcysteine, S-tritylcysteine, S-(p-methylbenzyl)cysteine, S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine, O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine and O-benzyltyrosine.
Furthermore, A is not limited to groups introduced from raw materials derived from natural amino acid, but may satisfactorily be groups (for example, phenyl group and phenylthiomethyl group) introduced from raw materials derived from non-natural amino acid.
In accordance with the invention, preference is given to compounds wherein A is an aryl group with 6 to 15 carbon atoms, an aralkyl group with 7 to 20 carbon atoms or a group containing a hetero-atom in these carbon backbones; furthermore, preference is given to compounds wherein A is an aralkyl group with 7 to 20 carbon atoms or a group containing a hetero-atom in these carbon backbones. More specifically, preference is given to compounds wherein A is benzyl group, phenylthiomethyl group, 4-benzyloxyphenylmethyl group, isopropyl group, 2-methylpropyl group and 1-methylpropyl group; still furthermore, preference is given to compounds wherein A is benzyl group, phenylthiomethyl group and 4-benzyloxyphenylmethyl group. Compounds wherein A is benzyl group are particularly preferable.
The preferable process (a) is described below.
N-Carbamate-protected xcex2-aminoalcohol containing at least the diastereomer as an impurity and being represented by the general formula (1), namely the (2R, 3S) alcohol or (2S, 3R) alcohol, may be obtained by reducing (3S)-N-carbamate protected xcex1-aminohalomethylketone represented by the general formula (13) or (3R)-N-carbamate-protected aminohalomethylketone represented by the general formula (14) 
{in the formula, R, A and X represent the same meanings as described above}
{in the formula, R, A and X represent the same meanings as described above}.
It has been known that the ratio of the generated (2R, 3S) alcohol and (2S, 3S) alcohol through reduction varies depending on the type of a reducing agent. By selecting an appropriate reducing agent, the ratio of the diastereomer as an impurity can be suppressed at some extent (see T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update). This is the same for the ratio of the (2S, 3R) alcohol and the (2R, 3R) alcohol in the case of the reduction of (3R)-N-carbamate-protected xcex1-aminohalomethylketone.
Preferable reducing agents include for example lithium aluminum tri-tert-butoxyhydride, (+)-B-chlorodiisopinocamphenylborane, and boron potassium trisec-butylhydride; particularly, lithium aluminum tri-tert butoxyhydride is preferable.
Herein, (3S)-N-protected xcex1-aminohalomethylketone and (3R)-N-protected xcex1-aminohalomethylketone can be produced by known methods, for example, such as the method including allowing amino acid ester with the amino group under protection, to react with a metal enolate prepared from xcex1-haloacetic acid, thereby eliminating carbonate (see International Patent Publication WO 96/23756).
When the reaction mixture recovered by the method is subjected for example to the process (a) of the invention, the ratio of the objective (2R, 3S) alcohol or (2S, 3R) alcohol is preferably high. Even when the ratio of each of these diastereomers to the (2R, 3S) alcohol or (2S, 3R) alcohol is high, the method of the invention is applicable.
The method of the invention is applicable to a mixture at a molar ratio of (2S, 3S) alcohol/(2S, 3R) alcohol or (2R, 3R) alcohol/(2S, 3R) alcohol, below 100, preferably below 1, more preferably below xc2xd, particularly preferably below ⅓.
The aromatic hydrocarbon solvent to be used at the process (a) includes for example benzene, xylene, toluene and an appropriate mixture solvent of these solvents Particularly, xylene, toluene and an appropriate mixture solvent of these solvents are preferable; toluene is particularly preferable.
The aryl halide solvent to be used at the process (a) includes for example chlorobenzene, bromobenzene and appropriate mixture solvents of these solvents. Particularly, chlorobenzene is preferable.
The saturated hydrocarbon solvent to be used at the process (a) includes for example n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, isohexane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, petroleum ether, and appropriate mixture solvents of these solvents.
Particularly preferable solvents include n-hexane, n-heptane, cyclohexane, methylcyclohexane and appropriate mixtures of these solvents. Particularly, n-heptane is preferable.
The aqueous mixture solvent at the process (a) means a mixture solvent of a water-miscible organic solvent with water; the organic solvent miscible with water includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran. Methanol, ethanol, 2-propanol, acetone and appropriate mixture solvents of these solvents are preferable; furthermore, methanol, ethanol, 2-propanol and appropriate mixture solvents of these solvents are more preferable; and particularly, 2-propanol is preferable. Acetone and 2-propanol can be used singly, but preferably, they are used in the form of mixture solvents with water.
The composition ratio of water and an organic solvent is not particularly limited, but the ratio is preferably 5 to 95%, more preferably 25 to 90% (% is expressed as the volume ratio of an organic solvent in a mixture solvent).
More preferable are aromatic hydrocarbon solvents and aqueous mixture solvents among the solvents for use at the process (a). Particularly, aromatic hydrocarbon solvents are preferable. Among them, more preferable are toluene, xylene and a mixture solvent of 2-propanol with water; particularly, toluene is preferable.
As far as the advantages of the invention are not adversely influenced, other solvents may be added to the solvent for use as the solvent at the process (a).
At the process (a) of the invention, the (2R, 3S) alcohol or (2S, 3R) alcohol at least containing the diastereomer as an impurity is dissolved in aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, acetone, 2-propanol or aqueous mixture solvent, to remove insoluble matters. More specifically, a state such that the objective (2R, 3S) alcohol or (2S, 3R) alcohol is dissolved in these solvents while the diastereomer is present as insoluble matters, is to be realized, despite any procedure adopted.
For example, a solvent including at least one or more selected from aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol is added to the (2R, 3S) alcohol or (2S, 3R) alcohol at least containing the diastereomer as an impurity, for agitation. Then, the (2R, 3S) alcohol or (2S, 3R) alcohol is relatively readily dissolved in these solvents, while the diastereomer thereof is slightly soluble and turns insoluble matters to be generally prepared as a form of slurry, although the form depends on the content of impurities, the solvent volume and the temperature. For example, at a high temperature above ambient temperature, the slurry form is modified into a solution state, which is then cooled down to an appropriate temperature to deposit the diastereomer as an impurity.
For example, for subjecting the reaction mixture obtained by reduction to the process (a) of the present invention, the reaction solvent is preferably concentrated or more preferably sufficiently evaporated after the reduction is terminated; and subsequently, the aforementioned solvent is added to the resulting residue, from the respect of purification efficiency.
The quantity of solvent to be added is not particularly limited, but is preferably at a weight 1- to 50-fold the weight of a mixture to be subjected to the process (a). The temperature for agitation is not particularly limited and is for example a temperature at xe2x88x9220xc2x0 C. to a temperature below the boiling point of the solvent to be used. The temperature preferably varies, depending on the type and quantity of the solvent to be used. So as to decrease the loss of the objective compound, for example, wherein a saturated hydrocarbon solvent is used, the solvent is heated to an appropriate temperature above ambient temperature and below the boiling point of the solvent (preferably, 35xc2x0 C. to 70xc2x0 C.), preferably, while insoluble matters are filtered under heating as they are. In case that an aromatic hydrocarbon solvent or aryl halide solvent is used, for example, the temperature of the solvent is controlled to below ambient temperature down to an appropriate temperature (for example, about xe2x88x9220xc2x0 C.), preferably, while insoluble matters are filtered. In case that an aqueous mixture solvent is used, for example, insoluble matters are satisfactorily filtered within a range of about 0xc2x0 C. to 50xc2x0 C., which varies depending on the mixing ratio of water and a solvent. The agitation time is not particularly limited but is preferably 10 minutes to 6 hours; more preferably 30 minutes to 5 hours, and most preferably, 1 hour to 4 hours.
A person with an ordinary skill in the art can readily determine preferable conditions depending on the solvent to be used, on the basis of the description of the specification.
Then, insoluble matters are preferably removed, e.g., by filtration. The (2S, 3S) alcohol or (2R, 3R) alcohol as an impurity is then removed as solid. By evaporation of the solvent in the filtrate, the (2R, 3S) alcohol or (2S, 3R) alcohol can be obtained. By cooling the filtrate, the objective compound can satisfactorily be isolated by crystallization. If necessary, the solvent of the filtrate is removed by azeotropic distillation for the following reaction process. And if necessary, the filtrate is used at the following reaction process after the filtrate is concentrated or as it is.
The purification procedures described above can satisfactorily be repeated at plural times, if necessary, in case that mixtures at a high impurity content are purified. Additionally, and optionally, the purification procedures may satisfactorily be effected in combination with other purification procedures known to a person with an ordinary skill in the art. For the synthesis of the objective compound for example through reduction, as described above, the ratio of the diastereomer as an impurity can be suppressed at a certain degree by selecting an appropriate reducing agent, so that single purification procedure may afford highly purified objective compound.
According to the process (a) of the invention, the (2R, 3S) alcohol or (2S, 3R) alcohol as the objective compound can be efficiently purified and isolated by simple procedures; the content of the diastereomer as an impurity can be reduced below 6%, which is described as impossible in the above reference.
More specifically, the solid separated as insoluble matters is a solid containing the (2S, 3S) alcohol or (2R, 3R) alcohol as the principal component, although the solid generally contains a certain content of the (2R, 3S) alcohol or (2S, 3R) alcohol. The solid is purified by using known purification methods such as Soxhlet extraction, the process (a) of the invention or a combination of these methods if necessary; otherwise, these purification methods can be repeated, if necessary, to thereby afford highly purified (2S, 3S) alcohol or (2R, 3R) alcohol.
The preferable process (b) is described below.
By treating the N-carbamate-protected xcex2-aminoalcohol represented by the general formula (1) with a base, the N-carbamate-protected xcex2-aminoalcohol can be converted to N-carbamate-protected xcex2-aminoepoxide as an intermediate at a progressed stage, which is represented by the general formula (2) (see the references described above).
The base preferably includes potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium hydride; sodium hydroxide and potassium carbonate are particularly preferable.
The reaction solvent preferably includes protonic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1,2-dimethylpropanol and water or non-protonic solvents such as acetone, tetrahydrofuran and acetonitrile, singly or in mixture; ethanol, a mixture solvent of ethanol and water, a mixture solvent of 2-propanol and water, and a mixture solvent of acetone and water are particularly preferable.
The amount of the base to be used varies depending on the type of the base to be used and the combination of solvents, but the amount is generally 1 to 10 equivalents, preferably 1 to 5 equivalents. The reaction temperature varies depending on the type of the base and the combination of solvents, but the temperature is generally xe2x88x9210 to 80xc2x0 C., preferably 0 to 60xc2x0 C. The reaction time is not particularly limited, but the reaction time is preferably about 10 minutes to about 50 hours, more preferably about 30 minutes to about 40 hours, and most preferably about 1 hour to about 30 hours.
The reaction is preferably performed under agitation; after termination of the reaction, acid is satisfactorily added to quench the reaction. The acid, preferably, includes hydrochloric acid, sulfuric acid, acetic acid, citric acid and aqueous potassium hydrogen sulfate solution.
The (2R, 3S) epoxide or (2S, 3R) epoxide may be isolated from the reaction solvent by methods such as extraction, but preferably by the crystallization method at the process (d) described below. Further, so as to further remove the impurity diastereomer, the process (c) described below is preferably effected.
Preferably, for performing the process (c) or process (d) subsequent to the process (b), the reaction solvent is concentrated or substituted with an appropriate solvent, if necessary, without extraction, for use at the following process. Additionally, crystallization may be performed by the method of the process (d) after the process (b), followed by the process (c), to obtain N-carbamate-protected xcex2-aminoepoxide crystal, again at the process (d). In such manner, the same processes can be performed at plural times, if necessary.
The preferable process (c) is described below.
N-Carbamate-protected xcex2-aminoepoxide containing the diastereomer as an impurity, as represented by the general formula (2), is treated with an acid, to convert the impurity diastereomer to oxazolidin-2-one represented by the general formula (3), if necessary, which is then separated and removed in water or an aqueous mixture solvent.
When N-carbamate-protected xcex2-aminoepoxide represented by the general formula (2), namely the (2R, 3S) epoxide or (2S, 3R) epoxide, is treated with an acid, the diastereomer (2S, 3S) epoxide or (2R, 3R) epoxide is relatively rapidly converted to oxazolidin-2-one derivative represented by the general formula (3) (see Reference Examples 4 and 5 described below). Because the reaction velocity of the (2R, 3S) epoxide or (2S, 3R) epoxide is slow, the diastereomer as an impurity can be removed, preferentially, by removing the resulting oxazolidin-2-one derivative from the system (Tetrahedron Letters, Vol. 35, No. 28, pp. 4939-4942, 1994).
As the acid, for example, preference is given to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acidic ion exchange resin (ion exchange resin acid catalyst), acid alumina (alumina acid catalyst), acid zeolite (zeolite acid catalyst) and acid china clay; solid acids insoluble in solvents such as p-toluenesulfonic acid, acid ion exchange resin, acid zeolite, and acid china clay, are preferable. Solid acids insoluble in solvents suitable for the reaction, such as acid ion exchange resin, acid alumina, acid zeolite and acid china clay are readily removed, while byproducts generated via the reaction of the epoxide with acids can be removed under filtration, simultaneously. Thus, these solid acids are particularly preferable.
The preferable reaction solvent includes methanol, ethanol, 2-propanol, 1,2-dimethylpropanol, water, acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, dichloroethane, diethyl ether, benzene, toluene, hexane and heptane, singly or in mixture; non-protonic solvents such as dichloromethane, toluene, acetone and acetonitrile are particularly preferable.
The quantity of acid varies, depending on the type of the acid used, and is not particularly limited. With respect to the quality (purity) and yield of the objective (2R, 3S) or (2S, 3R) epoxide, a person with an ordinary skill in the art can easily determine an appropriate amount without undue experimentation.
When p-toluenesulfonic acid is used, for example, about 1 to 5 equivalents of the acid to the (2S, 3S) or (2R, 3R) epoxide contained as an impurity is preferably used. In case that strong acid ion exchange resins and acid zeolite are used, additionally, 1 to 200% by weight of the acids is preferably used to the (2R, 3S) or (2S, 3R) epoxide to be treated.
The reaction temperature varies, depending on a combination of acids and solvents, but the reaction temperature is generally xe2x88x9210 to 120xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is preferably about 10 minutes to 50 hours, more preferably about 30 minutes to about 40 hours, and most preferably about 1 hour to about 30 hours, with no specific limitation. The objective (2R, 3S) or (2S, 3R) epoxide reacts just slowly with such acid and is converted to oxazolidin-2-one, so the reaction for a period more than necessary is not preferable. Like the quantity of the acid to be used, an appropriate reaction time can readily be determined by a person with an ordinary skill in the art, by monitoring the concentration of the diastereomer in the reaction solution, with respect to the desired quality (purity) and yield of the objective compound.
Through the acid treatment described above, the diastereomer contained as an impurity is preferentially converted to oxazolidin-2-one derivative. 
Because the oxazolidin-2-one derivative is soluble in water, the oxazolidin-2-one derivative can be readily separated and removed by dissolving the oxazolidin-2-one derivative in water or an aqueous mixture solvent. The aqueous mixture solvent means a mixture solvent of a water-miscible organic solvent with water; the organic solvent includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran.
The method for separating and removing the oxazolidin-2-one derivative in water or an aqueous mixture solvent includes extraction or crystallization, but with no specific limitation. Wherein the process (d) is performed after the process (c), crystallization is performed in an aqueous mixture solvent, so the oxazolidin-2-one derivative is separated and removed in the mother liquor. Therefore, generally, it is not necessary to preliminarily remove the oxazolidin-2-one derivative by extraction and the like, prior to the process (d).
The preferable extraction case is described herein below. In this case, water is particularly preferable as the solvent for dissolving the oxazolidin-2-one derivative.
When solvent-soluble acids, such as p-toluenesulfonic acid, are used in the acid treatment process, for example, aqueous basic solutions such as sodium hydrogen carbonate are added under agitation, if necessary, after an appropriate reaction time, to terminate the reaction.
Thereafter, the organic layer is optionally evaporated, so as to substitute the organic layer with a solvent preferable for extraction. The extraction solvent preferably includes toluene, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and dichloromethane; with respect to the separation and removal efficacy of the oxazolidin-2-one into an aqueous phase, toluene is particularly preferable. For extraction, preferably, insoluble matters in the organic layer or in the aqueous phase are preliminarily filtered off. After extraction, the organic layer is separated and preferably rinsed further in water, to efficiently remove (4S, 5R) or (4R, 5S) oxazolidin-2-one.
When solvent-insoluble acids, such as ion exchange resin and acid zeolite, are used, these acids can be removed under filtration to terminate the reaction. Thereafter, the organic solvent is optionally evaporated, so as to substitute the organic solvent with a solvent preferable for extraction. The extraction solvent preferably includes toluene, tert-butyl methyl ether, ethyl acetate, isopropyl acetate and dichloromethane; with respect to the separation and removal efficacy of the oxazolidin-2-one into the aqueous phase, toluene is particularly preferable. Then, water or aqueous mixture solvents are added for extraction; then, preferably, insoluble matters in the organic layer or in the aqueous layer are preliminarily filtered off. After extraction, the organic layer is separated and preferably rinsed further in water, to efficiently remove (4S, 5R) or (4R, 5S) oxazolidin-2-one.
By the method of the process (c) described above, the diastereomer as an impurity can be removed at a high efficiency. After the method of the process (a) of preliminarily removing the diastereomer, (2R, 3S) or (2S, 3R) epoxide, from which the diastereomer has been greatly removed, can be obtained by the process (c). Through the processes (a) and (c) of the invention or via the process (d) after these processes, the (2R, 3S) or (2S, 3R) epoxide can be obtained with a content of the diastereomer as an impurity below 3%, preferably below 2% and more preferably below 1%. The (2R, 3S) or (2S, 3R) epoxide thus afforded can be obtained as solid by evaporating the organic layer under reduced pressure. If necessary, further, the resulting solid can be purified with adsorption resins and the like. By the process (d) described below, the crystal of the (2R, 3S) or (2S, 3R) epoxide at a high purity can be recovered by such industrially advantageous method.
The preferable process (d) is described below.
Through crystallization of the (2R, 3S) or (2S, 3R) epoxide in an aqueous mixture solvent, the crystal at high purity can be obtained.
Firstly, an aqueous mixture solvent is added to the (2R, 3S) or (2S, 3R) epoxide. The aqueous mixture solvent means a mixture solvent of a water-miscible organic solvent with water; and the organic solvent includes methanol, ethanol, 1-propanol, 2-propanol, acetone, 2-butanone, acetonitrile and tetrahydrofuran. Particular preference is given to methanol, ethanol, 2-propanol, acetonitrile and acetone. The composition ratio of water and the organic solvent is not particularly limited but is preferably at 5 to 95%, more preferably at 25 to 85% (% is expressed as the ratio of the organic solvent in the mixture solvent).
The volume of the aqueous mixture solvent to be used is not particularly limited, but for example, the solvent of a volume of 2 to 20 ml to 1 g of for example the (2R, 3S) or (2S, 3R) epoxide can be used.
By subsequently cooling of the mixture, the (2R, 3S) or (2S, 3R) epoxide is crystallized.
The temperature for crystallization is preferably xe2x88x9240xc2x0 C. to 25xc2x0 C., particularly preferably xe2x88x9220xc2x0 C. to 10xc2x0 C. The crystallization then is performed, satisfactorily, under agitation or while left to stand alone. The crystallization is preferably performed under agitation, however. Generally, the (2R, 3S) or (2S, 3R) epoxide is not easily crystallized even in the aqueous mixture solvent which is comparatively good solvent for crystallizing (2R, 3S) or (2S, 3R) epoxide in comparison with other solvents. However, the crystallization may be easily performed by adding the seed crystal under the aqueous mixture solvent.
Optionally, to enhance the purification effect, the resulting crystal is heated to about 10xc2x0 C. to about 40xc2x0 C. to partially dissolve the crystal, which is again cooled to xe2x88x9220xc2x0 C. to 10xc2x0 C., for crystallization. The resulting crystal is preferably washed with water and the like. The process (d) enables efficient removal of the highly polar impurity into the mother liquor. Thus, highly pure (2R, 3S) or (2S, 3R) epoxide can be obtained.
Because the diastereomer (2S, 3S) or (2R, 3R) epoxide is hardly removed even by crystallization, as described above, more highly pure (2R, 3S) or (2S, 3R) epoxide can be recovered by performing the processes (a) and (b), or the process (c), or a combination of the processes (a), (b) and (c). If necessary, additionally, the process (d) may satisfactorily be carried out at plural times.